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21.
Homozygosity mapping of Portuguese and Japanese forms of ataxia-oculomotor apraxia to 9p13, and evidence for genetic heterogeneity 总被引:4,自引:0,他引:4
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Moreira MC Barbot C Tachi N Kozuka N Mendonça P Barros J Coutinho P Sequeiros J Koenig M 《American journal of human genetics》2001,68(2):501-508
Ataxia with oculomotor apraxia (AOA) is characterized by early-onset cerebellar ataxia, ocular apraxia, early areflexia, late peripheral neuropathy, slow progression, severe motor handicap, and absence of both telangiectasias and immunodeficiency. We studied 13 Portuguese families with AOA and found that the two largest families show linkage to 9p, with LOD scores of 4.13 and 3.82, respectively, at a recombination fraction of 0. These and three smaller families, all from northern Portugal, showed homozygosity and haplotype sharing over a 2-cM region on 9p13, demonstrating the existence of both a founding event and linkage to this locus, AOA1, in the five families. Three other families were excluded from this locus, demonstrating nonallelic heterogeneity in AOA. Early-onset cerebellar ataxia with hypoalbuminemia (EOCA-HA), so far described only in Japan, is characterized by marked cerebellar atrophy, peripheral neuropathy, mental retardation, and, occasionally, oculomotor apraxia. Two unrelated Japanese families with EOCA-HA were analyzed and appeared to show linkage to the AOA1 locus. Subsequently, hypoalbuminemia was found in all five Portuguese patients with AOA1 with a long disease duration, suggesting that AOA1 and EOCA-HA correspond to the same entity that accounts for a significant proportion of all recessive ataxias. The narrow localization of AOA1 should prompt the identification of the defective gene. 相似文献
22.
High germinal instability of the (CTG)n at the SCA8 locus of both expanded and normal alleles 总被引:3,自引:0,他引:3
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Silveira I Alonso I Guimarães L Mendonça P Santos C Maciel P Fidalgo De Matos JM Costa M Barbot C Tuna A Barros J Jardim L Coutinho P Sequeiros J 《American journal of human genetics》2000,66(3):830-840
The autosomal dominant spinocerebellar ataxias (SCAs) are a group of late-onset, neurodegenerative disorders for which 10 loci have been mapped (SCA1, SCA2, SCA4-SCA8, SCA10, MJD, and DRPLA). The mutant proteins have shown an expanded polyglutamine tract in SCA1, SCA2, MJD/SCA3, SCA6, SCA7, and DRPLA; a glycine-to-arginine substitution was found in SCA6 as well. Recently, an untranslated (CTG)n expansion on chromosome 13q was described as being the cause of SCA8. We have now (1) assessed the repeat size in a group of patients with ataxia and a large number of controls, (2) examined the intergenerational transmission of the repeat, and (3) estimated the instability of repeat size in the sperm of one patient and two healthy controls. Normal SCA8 chromosomes showed an apparently trimodal distribution, with classes of small (15-21 CTGs), intermediate (22-37 CTGs), and large (40-91 CTGs) alleles; large alleles accounted for only0.7% of all normal-size alleles. No expanded alleles (>/=100 CTGs) were found in controls. Expansion of the CTG tract was found in five families with ataxia; expanded alleles (all paternally transmitted) were characterized mostly by repeat-size contraction. There was a high germinal instability of both expanded and normal alleles: in one patient, the expanded allele (152 CTGs) had mostly contraction in size (often into the normal range); in the sperm of two normal controls, contractions were also more frequent, but occasional expansions into the upper limit of the normal size range were also seen. In conclusion, our results show (1) no overlapping between control (15-91) and pathogenic (100-152) alleles and (2) a high instability in spermatogenesis (both for expanded and normal alleles), suggesting a high mutational rate at the SCA8 locus. 相似文献
23.
Amelia O. Clive Clare E. Hooper Anthony J. Edey Anna J. Morley Natalie Zahan-Evans David Hall Iain Lyburn Paul White Jeremy P. Braybrooke Iara Sequeiros Stephen M. Lyen Tim Milton Brennan C. Kahan Nick A. Maskell 《PloS one》2015,10(3)
Introduction
Animal studies have shown Zoledronic Acid (ZA) may diminish pleural fluid accumulation and tumour bulk in malignant pleural disease (MPD). We performed a pilot study to evaluate its effects in humans.Methods
We undertook a single centre, double-blind, placebo-controlled trial in adults with MPD. Patients were randomised (1:1) to receive 2 doses of intravenous ZA or placebo, 3 weeks apart and were followed-up for 6 weeks. The co-primary outcomes were change in Visual Analogue Scale (VAS) score measured breathlessness during trial follow-up and change in the initial area under the curve (iAUC) on thoracic Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI) from randomisation to week 5. Multiple secondary endpoints were also evaluated.Results
Between January 2010 and May 2013, 30 patients were enrolled, 24 randomised and 4 withdrew after randomisation (1 withdrew consent; 3 had a clinical decline). At baseline, the ZA group were more breathless, had more advanced disease on radiology and worse quality of life than the placebo group. There was no significant difference between the groups with regards change in breathlessness (Adjusted mean difference (AMD) 4.16 (95%CI −4.7 to 13.0)) or change in DCE-MRI iAUC (AMD −15.4 (95%CI −58.1 to 27.3). Two of nine (22%) in the ZA arm had a >10% improvement by modified RECIST (vs 0/11 who received placebo). There was no significant difference in quality of life measured by the QLQ-C30 score (global QOL: AMD -4.1 (-13.0 to 4.9)), side effects or serious adverse event rates.Conclusions
This is the first human study to evaluate ZA in MPD. The study is limited by small numbers and imbalanced baseline characteristics. Although no convincing treatment effect was identified, potential benefits for specific subgroups of patients cannot be excluded. This study provides important information regarding the feasibility of future trials to evaluate the effects of ZA further.Trial Registration
UK Clinical Research Network ID 8877 ISRCTN17030426 www.isrctn.com 相似文献24.
Ferro A Carvalho AL Teixeira-Castro A Almeida C Tomé RJ Cortes L Rodrigues AJ Logarinho E Sequeiros J Macedo-Ribeiro S Maciel P 《Biochimica et biophysica acta》2007,1773(11):1619-1627
Machado-Joseph disease (MJD/SCA3) is an autosomal dominant neurodegenerative disease caused by the expansion of a CAG tract in the coding portion of the ATXN3 gene. The presence of ubiquitin-positive aggregates of the defective protein in affected neurons is characteristic of this and most of the polyglutamine disorders. Recently, the accumulation of the neural precursor cell expressed developmentally downregulated 8 (NEDD8), a ubiquitin-like protein, in the inclusions of MJD brains was reported. Here, we report a new molecular interaction between wild-type ataxin-3 and NEDD8, using in vitro and in situ approaches. Furthermore, we show that this interaction is not dependent on the ubiquitin-interacting motifs in ataxin-3, since the presence of the Josephin domain is sufficient for the interaction to occur. The conservation of the interaction between the Caenorhabditis elegans ataxin-3 homologue (atx-3) and NEDD8 suggests its biological and functional relevance. Molecular docking studies of the NEDD8 molecule to the Josephin domain of ataxin-3 suggest that NEDD8 interacts with ataxin-3 in a substrate-like mode. In agreement, ataxin-3 displays deneddylase activity against a fluorogenic NEDD8 substrate. 相似文献
25.
26.
Characterization of alkaline proteases from a novel alkali-tolerant bacterium Bacillus patagoniensis
Nelda Olivera Cynthia Sequeiros Faustino Siñeriz Javier D. Breccia 《World journal of microbiology & biotechnology》2006,22(7):737-743
Summary The extracellular proteolytic activity produced by a moderately alkaliphilic bacterium, Bacillus patagoniensis PAT 05T, was characterized. This strain, grown in a highly alkaline and saline medium, produced important levels of proteolytic activity.
SDS-PAGE and zymogram analyses revealed two proteolytic active bands. Through isoelectricfocusing (IEF)-zymogram, an active
band with alkaline pI and two slighter active bands with acid pI values were detected. The alkaline active enzyme in the IEF
was purified and characterized. It showed a molecular mass of 29.4 kDa and its pI value was >‰10.3. Proteolytic activity of
the culture supernatant showed an optimal temperature of approximately 60 °C and a plateau of maximum activity between pH
9.0 and 12.0. Such activity was not affected by H2O2 (10% v/v), 1,10-phenanthroline (10 mM), Triton X-100 (1% v/v) and Tween 20 (1% v/v), under the assay conditions. More than
80% of the activity was retained in 10 mM EDTA, 73% in 1 % (w/v) SDS and 63% in 2 M NaCl. The enzyme was inhibited by PMSF,
indicating serine-protease activity. The proteolytic activity of the crude supernatant was thermosensitive with a half-life
of 2.3 min at 70 °C, while high activity was detected at moderate temperatures. Considering PAT 05T proteolytic activity characteristics, such as high optimum pH, high stability and residual activity in presence of oxidant,
surfactant and chelating agents, this strain could be a potential source of enzymes for use as additives in detergent formulations
or in the leather industry. 相似文献
27.
Jani Takatalo Jaro Karppinen Simo Taimela Jaakko Niinim?ki Jaana Laitinen Roberto Blanco Sequeiros Dino Samartzis Raija Korpelainen Simo N?yh? Jouko Remes Osmo Tervonen 《PloS one》2013,8(2)
Purpose
To evaluate whether midsagittal (abdominal) obesity in magnetic resonance imaging (MRI), waist circumference (WC) and body fat percentage are associated with lumbar disc degeneration in early adulthood.Methods
We obtained the lumbar MRI (1.5-T scanner) of 325 females and 233 males at a mean age of 21 years. Lumbar disc degeneration was evaluated using Pfirrmann classification. We analysed the associations of MRI measures of obesity (abdominal diameter (AD), sagittal diameter (SAD), ventral subcutaneous thickness (VST), and dorsal subcutaneous thickness (DST)), WC and body fat percentage with disc degeneration sum scores using ordinal logistic regression.Results
A total of 155 (48%) females and 147 (63%) males had disc degeneration. AD and SAD were associated with a disc degeneration sum score of ≥3 compared to disc degeneration sum score of 0–2 (OR 1.67; 95% confidence interval (CI) 1.20–2.33 and OR 1.40; 95% CI 1.12–1.75, respectively) among males, but we found no association among females. WC was also associated with disc degeneration among males (OR 1.03 per one cm; 95% CI 1.00–1.05), but not among females.Conclusion
Measures of abdominal obesity in MRI and waist circumference were associated with disc degeneration among 21-year-old males. 相似文献28.
Diversity and enzyme properties of protease-producing bacteria isolated from sub-Antarctic sediments of Isla de Los Estados, Argentina 总被引:1,自引:0,他引:1
Protease-producing bacteria isolated from sub-Antarctic marine sediments of Isla de Los Estados (Argentina) were characterized,
and the thermal inactivation kinetics of their extracellular proteases compared. Isolates were affiliated with the genera
Pseudoalteromonas, Shewanella, Colwellia, Planococcus, and a strain to the family Flavobacteriaceae. Colwellia strains were moderate psychrophiles (optimal growth at about 15°C, maximum growth temperature at around 25°C). 16S rRNA phylogenetic
analysis revealed that these strains and Colwellia aestuarii form a distinct lineage within the genus. The remaining isolates were psychrotolerant and grew optimally between 20 and 25°C;
two of them represent potentially novel species or genus (16S rRNA < 97% sequence similarity). The thermostability of the
extracellular proteases produced by the isolates was analysed, and the inactivation rate constant (k
in), the activation energy (Eain) and the activation Gibbs free energy of thermal inactivation (ΔG
*
in) determined. ΔG
*
in, calculated at 30°C, varied between 97 and 124 kJ/mol. Colwellia enzyme extracts presented the highest thermosensitivity, while the most thermostable protease activity was shown by Shewanella spp. These results demonstrated that the stability to temperature of these enzymes varies considerably among the isolates,
suggesting important variations in the thermal properties of the proteases that can coexist in this environment. 相似文献
29.
Carolina Lemos Isabel Alonso José Barros Jorge Sequeiros José Pereira-Monteiro Denisa Mendon?a Alda Sousa 《PloS one》2012,7(11)
Aim
Our aim was to assess which specific factors are contributing to an increased risk of migraine in a group of 131 Portuguese families.Methods
We studied 319 first-degree relatives, using a multilevel approach to account for the dependency among members from the same family. We included in the model relative’s gender, the proband’s gender and age-at-onset, to evaluate if any of these variables were associated with relative’s affection status. We also included in the model proband’s migraine subtype. We further assessed female and male transmissions within the proband nuclear family.Results
Relatives’ gender was found to be a risk factor for migraine (Odds Ratio = 2.86; 95% CI = 1.75–4.67), with females at a higher risk. When splitting probands according to their migraine subtype, we found that none of the variables studied contributed to relatives of MA-probands affection-status. Our results also show a significant difference between proband’s transmission and the gender of the parents and offspring.Conclusions
With this study, we showed that gender is truly a risk factor for migraine and that a gender-biased transmission is also observed. This reinforce the importance of identifying genes associated with migraine that are modulated by genes located in the sex chromosomes and the study of mitochondrial DNA or X-chromosome and hormonal-related effects associated with migraine susceptibility. 相似文献30.
Lee JM Gillis T Mysore JS Ramos EM Myers RH Hayden MR Morrison PJ Nance M Ross CA Margolis RL Squitieri F Griguoli A Di Donato S Gomez-Tortosa E Ayuso C Suchowersky O Trent RJ McCusker E Novelletto A Frontali M Jones R Ashizawa T Frank S Saint-Hilaire MH Hersch SM Rosas HD Lucente D Harrison MB Zanko A Abramson RK Marder K Sequeiros J MacDonald ME Gusella JF 《American journal of human genetics》2012,90(3):434-444
Age at the onset of motor symptoms in Huntington disease (HD) is determined largely by the length of a CAG repeat expansion in HTT but is also influenced by other genetic factors. We tested whether common genetic variation near the mutation site is associated with differences in the distribution of expanded CAG alleles or age at the onset of motor symptoms. To define disease-associated single-nucleotide polymorphisms (SNPs), we compared 4p16.3 SNPs in HD subjects with population controls in a case:control strategy, which revealed that the strongest signals occurred at a great distance from the HD mutation as a result of "synthetic association" with SNP alleles that are of low frequency in population controls. Detailed analysis delineated a prominent ancestral haplotype that accounted for ~50% of HD chromosomes and extended to at least 938 kb on about half of these. Together, the seven most abundant haplotypes accounted for ~83% of HD chromosomes. Neither the extended shared haplotype nor the individual local HTT haplotypes were associated with altered CAG-repeat length distribution or residual age at the onset of motor symptoms, arguing against modification of these disease features by common cis-regulatory elements. Similarly, the 11 most frequent control haplotypes showed no trans-modifier effect on age at the onset of motor symptoms. Our results argue against common local regulatory variation as a factor influencing HD pathogenesis, suggesting that genetic modifiers be sought elsewhere in the genome. They also indicate that genome-wide association analysis with a small number of cases can be effective for regional localization of genetic defects, even when a founder effect accounts for only a fraction of the disorder. 相似文献